Starches are comprised of α-glucans (amylose and amylopectin in variable proportions, amounting to ˜82 to 89%), moisture (˜11 to 17%), lipids (cereal starches only, <1.5%) and protein (˜0.5%) with some α-glucan phosphate-esters (especially in potato amylopectin). Plants produce starches in different sizes and shapes which reflect the botanical origin. In rice starch for example, the granules are <5 μm in diameter while in potato starch they may exceed 50 μm. The amylose fraction of starches comprise predominantly linear α-(1-4)-glucan molecules with a molecular weight of ˜0.25 to 0.50 million Daltons. Amylopectin molecules are much larger with a molecular weight of a few million Daltons (probably 8-10 million Daltons) and comprise a heavily branched structure of small unit chains (˜15 to 80 glucose units long). The unit chains are like amylose α-(1-4)-glucans (˜95% of bonds) but are linked together by α-(1-6) bonds (˜5%). Native starch granules contain double helices of amylopectin which associate together to form crystalline laminates which are interspersed with amorphous amylopectin branch regions and amylose chains.
The properties of native starches from different botanical origins may be modified by genetic, chemical, enzymatic and/or physical processing. During the last few centuries, novel mutations have been developed where the ratio of amylose to amylopectin in the starches has been modified to create ‘high amylose’ starches where the α-glucan fraction may represent >70% amylose (<30% amylopectin) and ‘waxy’ starches where the amylopectin fraction may represent >70% amylopectin (<30% amylose). Modern methods of ‘transgenic’ technology may also be used to create novel glucans within starch granules with different chain lengths, distributions and potentially even sugar residues other than glucose. Chemical methods have been used to enhance the properties of starch granules where residues may be added by chemical bonding, stabilisation may be achieved by cross-linking or molecular weight may be reduced by hydrolysis (with for example acids). Glucose syrups may be made from starches by acid hydrolysis but are more often made by enzymatic hydrolysis (below). Here, amylases (specifically α-amylase) and amyloglucosidase can be used to produce syrups with variable proportions of α-dextrins, different chain lengths and sugars (glucose and maltose). Physically, starches may be pre-gelatinised (heated in water to remove crystallinity and dried to make ‘instant’ products) or damaged (e.g. milled to remove ordered structure) to moderate their functionality also.
Dextrins represent hydrolytic products of starches. They are produced using a number of approaches as discussed above.
Extensive acid hydrolysis may be used to produce low molecular weight dextrins (<degree of polymerisation, DP, ˜20) where they may be branched or linear, together with sugars in variable proportions. The extent of hydrolysis is described relative to the amount of reducing power compared to a standard dextrose solution (dextrose equivalence, DE). When glucose syrups are purchased they are defined in terms of DE which suit specific applications. These products are used extensively in the food industry in confectionery, desserts, drinks, cakes and pastries etc. where there is a requirement for sweetness and product ‘body’. In the pharmaceutical industry there is a similar need for glucose syrups in for examples pastilles and tinctures with a need for pure glucose (dextrose) in for example intra-venous products.
Less extensive acid hydrolysis of starches (with some transglucosidation and repolymerisation) is achieved by treating dry starches with acids and heating at high temperatures. These dextrin products are described as ‘pyrodextrins’ which readily disintegrate in water and progressively solubilise. They are classified as ‘white’, ‘yellow’ or ‘British Gums’. These dextrins have varying disintegrating and solubilising characteristics and have specific applications as for example tablet excipients.
Cyclodextrins are ring forms of dextrin oligomers. The rings may contain six, seven or eight glucose residues forming a hydrophobic core and hydrophilic exterior. Hydrophobic residues (e.g. drugs) may be located inside these cores and provide a vehicle for drug delivery. A number of manufacturers prepare cyclodextrins and their industrial utilisation is quite well established (below).
Unlike the pyrodextrins, α-(limit)-dextrins generated by α-amylase hydrolysis are not employed as high molecular weight products (where there is limited hydrolysis), either in the food or pharmaceutical sectors. Similarly, β-limit dextrins produced by hydrolysis of soluble starches (generating the dextrins from amylopectin and maltose sequentially from the α-glucan non-reducing ends discussed below) are not used extensively in these industries. The α-limit dextrins become more soluble as hydrolysis is extended which, although random, is initially restricted to starch amorphous regions. The β-limit dextrins are highly soluble as exterior chains of amylopectin have been hydrolysed (to maltose) leaving short stubs attached to the (high molecular weight) branched limit-dextrin residues. β-limit dextrins are not at present commercially available in significant quantities.
According to the National Starch web directory, a dextrin may be defined as:
‘Dextrins are starch hydrolysis products obtained in a dry roasting process either using starch alone or with trace levels of acid catalyst. The products are characterised by good solubility in water to give stable viscosities. Four types exist: White, Yellow, British Gums and Solution-stable dextrins.’
Note that in reference to this commercially accepted term, citations in patents referring to the use of ‘dextrins’ (e.g. Gregory (1983) and Gole et al (1994), as discussed below) exclude β-limit dextrins since they can only be produced in the solubilised and not the dry state.
The properties of different dextrins are, as discussed above, very different in terms of their chemical and physical properties. They also have different properties with respect to their potential to be hydrolysed by different enzymes. Comparisons are broadly made as follows:
Comparison of Properties of Different Dextrins
Note that commercial dextrins are produced by heating starches in the presence of a very small amount of acid which induces hydrolysis, transglucosidation and repolymerisation.
ProductChemicalPhysicalDextrincharacteristicspropertiespropertiesβ-limit dextrinWhite powderMolecularSoluble[Not a dextrinproduced byweight ofpowder withaccordinghydrolysingdextrin ~50%no granular orto commonsolubilisedthat ofcrystallinecommercial/amylopectinamylopectin.form - i.e.industrial usage(from starch)Incorporates noamorphous.of the term, seewith β-amylaseamylosedefinitionresidues.above]Maltose wouldbe present(from amyloseand amylopectinhydrolysis)unless removedby for exampledialysis orchromatography.British GumsDextrin,HydrolysedDark[Trueusually yellowstarchescoloured andcommercialor brown andincorporatingrelativelydextrin]darker thanresidues ofsoluble - standardamylose andespecially‘yellowamylopectinwhen heated - dextrins’which willin water.below. Powderincorporateform producedsomeby roasting~drytransglucosidationstarch at highandtemperatures repolymerisationat~neutral pH.MaltodextrinProduced fromBranchedSoluble[Not a dextrinextensive aciddextrinsdextrinsaccording toorcomprisingwithcommonα-amylase (α-α-(1-4) and α-reducingcommercial/limit dextrin)(1-6) bonds.power muchindustrial usagehydrolysis ofLow moleculargreater thanof the term, seestarch.weight (degreestarchdefinitionComponent ofofpolysaccharidesabove]glucose syrups.polymerisation,but lessDP, <~20)than freesolublesugars.branchedDextroseproduct.equivalence(DE), 5-20.White GumsDextrin,HydrolysedLight[Trueusually~white.starchescoloured andcommercialPowder formincorporatingrelativelydextrin]produced byresidues ofsoluble - roasting~dryamylose andespeciallystarch at relativelyamylopectinwhen heated - low temperatureswhich willin water.at low pH.incorporatesometransglucosidationandrepolymerisationYellow GumsDextrin,HighlyYellow(also referredyellow. Powderconvertedcoloured andto as Canaryform producedhydrolysedrelativelyGums)by roasting~drystarchessoluble - [Truestarch atincorporatingespeciallycommercialrelatively highresidues ofwhen heated - dextrin]temperatures atamylose andin water.low pH.amylopectinwhich willincorporatesometransglucosidationandrepolymerisation
Cyclodextrins and their derivatives have been used extensively in pharmaceutical applications and details may be found in a number of patent sources (e.g. Uekama et al, 1989).
As discussed above, amylopectin can be converted to β-limit dextrin by conversion with β-amylase. This enzyme works from the non-reducing end of the amylopectin molecule hydrolysing the exterior (external) chains leaving stubs (G2-G3) attached to the β-limit dextrin. Typically, 50-60% of the amylopectin is hydrolysed in this way (converted to maltose) reducing the molecular weight accordingly (from for example ˜8 million Daltons to ˜3 million). These products are readily hydrolysed by α-amylase and especially amyloglucosidase to glucose. The amylopectin molecule is sparingly soluble and slowly retrogrades (crystallises) from solution. The β-limit dextrin, is however, highly soluble and would not readily retrograde from solution.
One important application of solid dose formulations is the application in rapid release oral dose (buccal melt) type formulations. These products have been described by Ohno et al (1999) in relation to their buccal type formulations and those of their competitors. The proposed advantage of the Ohno et al (1999) technology over their competitors is the capacity to make solid formulations that might disintegrate rapidly. The technology describes the use of a pharmaceutically active agent, erythritol, crystalline cellulose and a disintegrant.
Fast dissolving formulations have been described by Makino et al (1993) where they describe the use of an active ingredient, a carbohydrate and a barely sufficient amount of water to moisten the surface of particles of the said carbohydrate into a tablet form and a fast dissolving tablet obtained by this method. The carbohydrate fraction is defined as to include sugar, starch-sugars, lactose, honey, sugar alcohols and tetroses with tablets which are porous with excellent digestibility, solubility and adequate strength. It is stated that the carbohydrate to be employed must be ‘soluble in water and does not adversely affect the active ingredient (for example, decomposition of the active ingredient)’. The disclosure concentrates on sugars as they would be expected to dissolve and disperse apart from the active ingredients in tablets without entrapment-type interactions upon hydration. The disclosed preference is to use ‘sucrose, glucose, maltitol, xylitol, erythritol and so on’ [sugar and sugar alcohols but no mention of oligo- or polysaccharides]. Also mentioned are ‘sugar, starch-sugars, lactose, honey, sugar-alcohols, tetroses, sucrose, coupling-sugars, fructooligosaccharides, palatinose and so on’. Sugars are elaborated as ‘glucose, maltose, powdered syrup, starch syrup, isomerised sugar (fructose) and so on’. For lactose they elaborate as ‘lactose, isomerised lactose (lactulose), reduced lactose (lactitol)’. For sugar alcohols they include sorbitol, mannitol, reduced malt syrup (maltitol), reduced starch saccharides, xylitol, reduced palatinose and so on’. Tetroses are defined as obtained from glucose fermentation.
Zydis is a technology platform owned by R P Scherer (now Cardinal Health) where fast dissolving formulations are manufactured by blending and dissolving an active ingredient with a polymer, sugar and other ingredients followed by freeze drying (lyophilisation or in the context of the patent description ‘sublimation’). Although some authors have proposed that freeze dried formulations are problematic and have proposed solvent extractable matrices or matrices incorporating solvent sublimation to add advantage (Gregory et al, 1983; Gole et al, 1994) the Zydis technology is still popular. Gregory et al (1983) and Gole et al (1994) discuss the use of dextrins in their (sublimed/freeze dried) delivery matrices but do not define which type of dextrin which is very confusing in view of the very different chemistries and physical properties of different dextrins. The authors do not have interests in tablet production (by compression) per se. In reality, only some dextrins would impart desirable characteristics (forming the appropriate structure and melt type characteristics) in these freeze dried matrix types whilst others would be detrimental. For example, the dextrins present in maltose syrups have a very low molecular weight and would be very different (size, shape, structure, solubility, reducing power, rheology, digestibility etc.) from dextrins produced from very limited (acid or α-amylase) hydrolysis of native starches. In fact, the only example Gregory (1983) cite is ‘dextrin’ (not type, source etc.) while the Gole et al (1994) application is based on (exemplified by) maltodextrin (which is generated by α-amylase but not β-amylase as previously discussed). It is apparent in these patents that the applicants do not understand the breadth of different chemical species and properties in different types of dextrins. Different dextrins have different properties and chemistries.